Members of the tumor necrosis factor receptor (TNFR) superfamily regulate a diverse range of cellular processes including cell proliferation, programmed cell death and immune responses. Characteristically, these receptors are transmembrane (type 1) glycoproteins having cysteine-rich subdomains in their extracellular, ligand binding domain (Gruss (1996) Int. J. Clin. Lab. Res. 26:143-159).
A recently identified member of the TNFR superfamily is the herpesvirus entry mediator (HVEM) (Montgomery et al. (1996) Cell 87:427-436). HVEM mediates the entry of many strains of herpes simplex virus (HSV) into cells. Studies have revealed that HSV initiates infection by binding cell surface glycosaminoglycans. To actually enter the cell, the virus requires mediator activity, which is provided by HVEM. HVEM interacts with the virus by binding to the envelope glycoprotein D (gD) and triggering membrane fusion (Whitbeck et al. (1997) J. Virol. 71:6083-6093; Montgomery et al., supra).
To date, two ligands of HVEM have been identified, LIGHT and Lymphotoxin .alpha. (LT.alpha.) (Mauri et al. (1998) Immunity, 8:21-30). LIGHT is a novel cytokine and is termed LIGHT because it shows homology to Lymphotoxins, exhibits Inducible expression and competes with HSV Glycoprotein D for HVEM, a receptor expressed by T lymphocytes. The second identified ligand of HVEM, LT.alpha., is expressed exclusively by T-cells, has 30% sequence identity to TNF, and competes with TNF for binding to the TNF1 receptor. The biological effects exerted by LT.alpha. are similar to those of TNF. However, unlike TNF, LT.alpha. usually acts as a local paracrine factor. LT.alpha. has been shown to be a potent activator of neutrophils. Accordingly, it is thought to be a regulator of acute phase inflammatory reactions. In addition, LT.alpha. facilitates leukocyte extravasation by increasing leukocyte adhesion and cytokine production.
Recent evidence suggests that HVEM may also play a role in regulating immune responses. Studies have revealed that HVEM can bind to several TNF receptor-associated factors (TRAFs). TRAFs activate stress activated protein kinase-1/c-Jun N-terminal kinase (JNK/SAPK), as well as the transcription factors, Nuclear Factor-KAPPA B (NF-kB), and transcription factor activator protein-1 (AP-1). These transcription factors in turn control the expression of multiple immune, inflammatory, and acute phase genes (Marsters et al. (1997) J. Biol. Chem. 272:14029-14032).